Alpha adrenergic receptors are plasma membrane receptors which are located in the peripheral and central nervous systems throughout the body. They are members of a diverse family of structurally related receptors which contain seven putative helical domains and transduce signals by coupling to guanine nucleotide binding proteins (G-proteins). These receptors are important for controlling many physiological functions and, thus, have been important targets for drug development during the past 40 years. Examples of alpha adrenergic drugs include clonidine, phenoxybenzamine and prazosin (for treatment of hypertension), naphazoline (for nasal decongestion), medetomidine (for veterinary analgesia), UK-14,304 and p-aminoclonidine (for glaucoma). However, most of these drugs produce undesirable side effects, possibly due to their interactions with other receptor subtypes. For example, clonidine is a well known centrally acting antihypertensive agent. However, it also produces untoward side effects such as analgesia, sedation, bradycardia and dry mouth which may be due to its lack of selectivity at .alpha..sub.2 receptors.
.alpha.-Adrenergic receptors were originally proposed to have only two (alpha and beta) subtypes (Berthelsen, S.; Pettinger W. Life Sci., 21, 595 (1977)). However, modern molecular biological and pharmacological techniques have led to the identification of at least 6 subtypes (.alpha..sub.1a, .alpha..sub.1b, .alpha..sub.1c, .alpha..sub.2a, .alpha..sub.2b, and .alpha..sub.2c) of the adrenergic receptors (Bylund, D. B., Trends Pharmacol. Sci., 9, 356 (1988)).
Among many other therapeutic indications, .alpha..sub.2 receptors are believed to modulate pain and behavioral depression by regulating locus coeruleus firing. In addition, .alpha..sub.2 receptors are well known to be involved in effects on blood pressure, heart rate, vasoconstriction and on glaucoma. However, it is not known which therapeutic indications are controlled by each of these subtypes.
The effects of .alpha..sub.2 receptor agonists on analgesia, anesthesia and sedation have been well documented for past 10 years (Pertovaara, A., Progress in Neurobiology, 40, 691 (1993)). For example, systematic administration of clonidine has been shown to produce antinociception in various species including human patients in addition to its well known sedative effects. Intrathecal and epidural administration of clonidine has also proved effective in producing antinociception. Another .alpha..sub.2 agonist, medetomidine, which has better .alpha..sub.2 /.alpha..sub.1 selectivity and is more potent at .alpha..sub.2 receptors than clonidine, has been extensively studied for its antinociception effect. In the spinally-initiated heat-induced tail flick test in rats, systemic administration of medetomidine produced a dose-dependent antinociception which could be totally reversed by .alpha..sub.2 receptor antagonists, atipamazole or idazoxan. Experimental studies of medetomidine on pain sensitivity in humans also indicated that this agent is very effective for ischemic pain, even though effective drug doses were high enough to produce sedation and considerable decreases in blood pressure.
Effects of .alpha..sub.2 receptor agonists in anaesthetic practice have also been investigated (Bloor, B. C.; Flacke, W. E., Anesth. Analg., 61, 741 (1982)). The sedative effect of .alpha..sub.2 agonists is regarded as good component of premedication. Another beneficial effect of .alpha..sub.2 agonists in anaesthetic practice is their ability to potentiate the anaesthetic action of other agents and to reduce anaesthetic requirements of other drugs during surgery. Studies shows that premeditation with 5 .mu.g kg.sup.-1 of oral clonidine administration reduced fentanyl requirements for induction and intubation by 45% in patients undergoing aortoccronary bypass surgery (Ghingnone, M., et al., Anesthesiology, 64, 36 (1986)).